Immunological basis in the pathogenesis and treatment of bladder cancer

Abstract

The pathogenesis and transition of normal urothelium into bladder carcinoma are multifactorial processes. Chronic inflammation causes initiation and progression of the underlying pathophysiology of invasive and metastatic cancer. A dichotomy is observed in the role of immune cells in bladder cancer. While the immune response defends the host by suppressing neoplastic growth, several immune cells, including neutrophils, macrophages and T-lymphocytes, promote tumor development and progression. The levels of human neutrophil peptide-1, -2 and -3, produced by neutrophils, increase in bladder cancer and might promote tumor angiogenesis and growth. The effect of macrophages is primarily mediated by pro-inflammatory cytokines, IL-6 and TNF-α. In addition, the underlying immunological mechanisms of two treatments, BCG and cytokine gene-modified tumor vaccines, and future directions are critically discussed.

Keywords:

• BCG
• bladder cancer
• dendritic cells
• macrophages
• neutrophils
• T cells
• tumor vaccines
• urothelial cell carcinoma

Disclaimer

The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Financial & competing interest disclosure

This work was supported by research grants from the National Institutes of Health, USA to DK Agrawal. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Further investigations are warranted on the proteins, transcription factors and genes that would help identify patients who will develop incurable muscle-invasive bladder cancer.

• Epithelial-mesenchymal transition (EMT) is an important part of bladder carcinogenesis, but the stage in the metastatic cascade during which EMT begins remains to be elucidated.

• Several cellular pathways initiate EMT; however, the patterns of specificity and mechanisms of regulation for these pathways remain unknown.

• The effectiveness of therapies targeting M1, M2 and tumor-associated macrophages function requires an increased understanding of the mechanisms underlying polarized macrophage activation as well as macrophage level maintenance in cancer tissue.

• Chemotherapy and radiation are effective treatments for bladder cancer, but it is unknown whether the necrosis and inflammation resulting from these procedures promotes cancer recurrence or remission.

• Twenty-five percent of patients are unresponsive to BCG. Further study should seek to characterize various factors that might be used in the identification of patients for which treatment would be unsuccessful and should thus be avoided.

• BCG has been extensively studied; however, the kinetics of chemokine secretion, immune cell recruitment and TNF-related apoptosis-inducing ligand buildup are unknown.

Notes